The present invention relates to a novel imidazole derivative represented by the following formula (1) which shows an inhibitory activity against farnesyl transferase: 
in which A, n1 and Y are defined as described below, or pharmaceutically acceptable salts or isomers thereof.
The present invention also relates to a process for preparation of the compound of formula (1), to intermediates which are used in the preparation of the compound of formula (1), and to a pharmaceutical composition comprising the compound of formula (1) as an active ingredient.
Mammalian Ras proteins act as molecular switches in the signalling events associated with cell growth and differentiation. The ras proto-oncogene family consists of three members, N-, K-, and H-ras, which code for highly homologous 4 types of proteins; i.e., H, N-ras proteins of 189 residues and two isomorphic K-ras-4B and K-ras-4A proteins of 188 and 189 residues, respectively. The chemical basis for the switch mechanism involves cycling of the protein between the inactive (off) guanosine diphosphate (GDP) bound state and the active (on) guanosine triphosphate (GTP) bound state (Bourne, H. R; Sanders, D. A.; McCormick. F.; Nature, 1991, 349, 117). Biochemical and structural studies have shown that point mutations of the residues 12, 13 and 61, positioned in the neighborhood of phosphoryl ground of GTP, resulting in the decrease of guanosine triphosphatase activity are associated with many human cancers, particularly, pancreatic cancer, urinary bladder carcinoma, colon cancer, etc. (Bos, J. L., Cancer Res., 1989, 49, 4682).
Ras protein is synthesized as a cytosolic precursor that ultimately localized to the cytoplasmic face of the plasma membrane after a series of posttranslational modification (Gibbs, J. B., Cell 1991, 65, 1). These series of biochemical modifications, by changing the electrical charge state or spacial structure to increase the hydrophobicity allow Ras protein to attach to cell membrane more easily. The first and obligatory step in the series is the addition of a farnesyl moiety to the cysteine residue of the C-terminal CAAX motif (C, cysteine; A, usually aliphatic residue; X, any other amino acid) in a reaction catalyzed by farnesyl protein transferase (FTase). This modification is essential for Ras function, as demonstrated by the inability of Ras mutants lacking the C-terminal cysteine to be farnesylated, to localize to the plasma, and to transform mammalian cells in culture (Hancock, J. F., Magee, A. I., Childs, J. E., Marshall, C. J., Cell 1989, 57, 1167). The subsequent posttranslational modifications, cleavage of the AAX residues, carboxyl methylation of the the farnesylated cysteine, and palmitoylation of the cysteines located upstream of the CAAX motif in H- and N-ras proteins are not obligatory for Ras membrane association or cellular transforming activity. Interestingly, K-ras-4B, different from H- and N-ras, has a multiple lysine rich region named polybasic domain, instead of having cysteine required for palmitoylation, thereby facilitating the farnesylated ras protein to bind to anionic lipid layer of cell membrane. The inhibitors of FTase that catalyzes the obligatory modification have therefore been suggested as anticancer agents for tumors in which Ras oncogene contributes to transformation (Buses, J. E. et al., Chemistry and Biology, 1995, 2, 787). A number of FTase inhibitors recently identified demonstrated potent and specific ability to block Ras farnesylation, signalling and transformation in transformed cells and tumor cell lines both in vitro and in animal models (Kohl. N. E. et. al., Proc. Natl. Acad. Sci. USA. 1994, 91, 9141; Kohl, N. E. et al., Nature Medicine, 1995, 1 792).
However, most of the inhibitors are related to CAAX motif as Ras substrate mimic and peptidic in nature or contain a sulfhydryl group (U.S. Pat. No. 5,141,851; Kohl, N. E. et. al., Science, 1993, 260, 1934; PCT/US95/12224, Graham et al.; Sebti, S. M. et. al., J. Biol. Chem., 1995. 270, 26802; James, G. L. et al., Science, 1993, 260, 1937; Bishop, W. R. et al., J. Biol. Chem., 1995, 270, 30611). Recently, a new type of peptidomimetic inhibitor imitating catalytic step of FTase has been reported (Poulter, C. D. et al., J. Am. Chem. Soc., 1996, 118, 8761). The chemical basis of the inhibitor design relates to the reaction mechanism. This is, transferring prenyl group by the enzyme is electrophilic displacement and the reaction requires (+) charge in a transition state.
These inhibitors previously described, however, possess limited activity and selectivity for inhibition of the oncogenic function of Ras proteins, particularly K-ras-4B, which is found to be most common in human cancer. Therefore, new inhibitor having the ability of effectively inhibiting K-ras activity is required.
With regard to the restenosis and vascular proliferative diseases, it has been shown that inhibition of cellular ras prevents smooth muscle proliferation after vascular injury in vivo (Indolfi C. et al., Nature Med., 1995, 1(6), 541-545). This report definitively supports a role for farnesyl transferase inhibitors in this disease, showing inhibition of accumulation and proliferation of vascular smooth muscle.
The present inventors have performed studies for developing a compound having the structural characteristics imitating an intermediate state of catalytic reaction of FTase and as a result found that imidazole derivatives according to the present invention can potently inhibit the enzyme.
Therefore, the object of the present invention is to provide an imidazole derivative of formula (1) which inhibits the activity of FTase, a process for preparation thereof, and an intermediate which can be used effectively for the preparation of the compound of formula (1).
It is another object of the present invention to provide a pharmaceutical composition comprising the compound of formula (1) as an active ingredient.
It is the first object of the present invention to provide an imidazole derivative represented by the following formula (1) which inhibit the activity of farnesyl transferase: 
in which
n1 represents an integer of 1 to 4,
A represents hydrogen; straight-chain or branched C1-C10-alkyl which may be optionally substituted by C3-C7-cycloalkyl or lower alkoxy; or a radical selected from the following group: 
wherein
R1 and R1xe2x80x2 independently of one another represent hydrogen, halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy, phenyl, benzyloxy, or lower alkyl which may be optionally substituted by C3-C6-cycloalkyl,
R2 represents hydrogen or lower alkyl, or represents xe2x80x94Exe2x80x94F wherein E is xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 and F is hydrogen; lower alkyl which may be optionally substituted by phenoxy or biphenyl; lower alkoxy which may be optionally substituted by aryl; phenyl; benzyl; benzyloxy; or amino which may be optionally substituted by lower allyl, benzyl or C5-C6-cycloalkyl,
R3 represents hydrogen, lower alkyl or phenyl,
R4 represents a radical selected from the following group: 
wherein
n2 and n3 independently of one another denote 0, 1, 2, 3 or 4,
R5 and R9 independently of one another represent hydrogen, lower alkyl, lower alkoxy, phenoxy, phenyl, hydroxy or halogen,
R6 and R8 independently of one another represent hydrogen, lower alkyl, lower alkoxy, phenoxy, phenyl, cyano, hydroxy or halogen,
R7 represents hydrogen; lower alkyl which may be optionally substituted by C3-C6-cycloalkyl; lower alkoxy; hydroxy; C3-C6-cycloalkyl; di(lower alkyl)amino; phenyl; phenoxy; or halogen,
R10 represents hydrogen, lower alkyl or lower alkoxy,
Y represents a radical selected from the following group: 
wherein
X represents O or S,
B represents hydrogen, or lower alkyl which may be optionally substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,
C represents hydrogen, or lower alkyl which may be optionally substituted by aryl; or represents a radical selected from the following group: 
wherein
R11 and R12 independently of one another represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy,
R13 and R14 independently of one another represent hydrogen, lower alkyl, aryl or 
wherein X is defined as previously described, n4 is an integer of 2 to 4 and R15 is lower alkyl,
D represents amino acid residue or lower alkyl ester of amino acid residue; or represents a radical selected from the following group: 
wherein
R10 is defined as previously described,
Q represents O, S, Sxe2x95x90O or SO2,
z represents O, S, Sxe2x95x90O, SO2, Cxe2x95x90O or Cxe2x95x90S, or represents CHxe2x80x94R20 or Nxe2x80x94R20(wherein R20 is hydrogen, lower alkyl or hydroxy),
n5 denotes an integer of 1 to 3,
R16 and R17 independently of one another represents hydrogen; aryl; lower alkyl which may be optionally substituted by aryl or cyanoaryl; or 
xe2x80x83wherein n4, Q and R10 are defined as previously described,
R18 and R19 independently of one another represents hydrogen; halogen; hydroxy; cyano; lower alkyl; lower alkoxy; alkoxyalkyl; alkylthio; hydroxycarbonyl; aminocarbonyl; aminothiocarbonyl; alkylsulfonyl; alkylthioalkyl; alkylthioalkyloxy; aryl; or oxy, thio, sulfonyl or lower alkyl substituted by aryl,
G represents a radical selected by the following group: 
wherein
R11 and R12 are defined as previously described,
I represents lower alkoxy, or represents a radical selected from the following group: 
wherein
R16, R17 and Z are defined as previously described,
L represents a radical selected from the following group: 
wherein Z and Q are defined as previously described,
provided that (1) n2 is other than 0 when R3 is hydrogen, and
(2) Y is other than 
xe2x80x83when A is 
or pharmaceutically acceptable salts or isomers thereof.
Particularly, the compound according to the present invention has a quite different structure from the known inhibitors for farnesyl transferase, and furthermore it does never include the thiol moiety.
In the definitions for the substituents of the compound of formula (1), the term xe2x80x9clower alkylxe2x80x9d means a straight-chain or branched alkyl having 1 to 4 carbon atoms which includes methyl, ethyl, isopropyl, isobutyl and t-butyl.
Since the compound of formula (1) according to the present invention may have asymmetric carbon atoms depending on the substituents, it can be present in the form of R or S isomer, racemate, or mixtures thereof. Thus, the present invention also includes all of these stereoisomers and their mixtures.
Also, the compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt Such salt includes non-toxic acid addition salt containing pharmaceutically acceptable anion, for example a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc., a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trofluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, asparagic acid, etc., or a salt with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; base addition salt for example a salt with pyridine or ammonia; and metal addition salt, for example, a salt with alkali metal or alkaline earth metal such as lithium salt. Further, the present invention includes a solvate of the compound of formula (1) such as alcoholate or hydrate thereof. They can be produced by conventional conversion methods.
Among the compound of formula (1) according to the present invention, the preferred compounds include those wherein
n1 represents an integer of 1 to 3,
A represents hydrogen; straight-chain or branched C1-C10-alkyl which may be optionally substituted by C3-C7-cycloalkyl or lower alkoxy; or a radical selected from the following group: 
wherein
R1 and R1xe2x80x2 independently of one another represent hydrogen, halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy, phenyl, benzyloxy, or lower alkyl which may be optionally substituted by C3-C6-cycloalkyl,
R2 represents hydrogen or lower alkyl, or represents xe2x80x94Exe2x80x94F wherein E is xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 and F is hydrogen; lower alkyl which may be optionally substituted by phenoxy or biphenyl; lower alkoxy which may be optionally substituted by aryl; phenyl; benzyl; benzyloxy; or amino which may be optionally substituted by lower alkyl, benzyl or C5-C6-cycloalkyl,
R3 represents hydrogen or lower alkyl,
R4 represents a radical selected from the following group: 
wherein
n2 and n3 independently of one another denote 0, 1, 2, 3 or 4,
R5, R6, R8 and R9 independently of one another represent hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen,
R7 represents hydrogen; lower alkyl which may be optionally substituted by C3-C6-cycloalkyl; lower alkoxy; hydroxy; C3-C6-cycloalkyl; or halogen,
R10 represents hydrogen, methyl or methoxy,
Y represents a radical selected from the following group: 
wherein
X represents O or S,
B represents hydrogen, or lower alkyl which may be optionally substituted by lower alkoxy or aryl,
C represents hydrogen, or lower alkyl which may be optionally substituted by aryl; or represents a radical selected from the following group: 
wherein
R11 and R12 independently of one another represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, aminocarbonyl, phenyl or phenoxy,
R13 and R14 independently of one another represent hydrogen, lower alkyl, aryl or 
R15 wherein X is defined as previously described, n4 is 2 and R15 is lower alkyl,
D represents amino acid residue or lower alkyl ester of amino acid residue; or represents a radical selected from the following group: 
wherein
R10 is defined as previously described,
Q represents O, S, Sxe2x95x90O or SO2,
Z represents O, S, Sxe2x95x90O, SO2 or Cxe2x95x90O, or represents CHxe2x80x94R20 or Nxe2x80x94R20(wherein R20 is hydrogen, lower alkyl or hydroxy),
n5 denotes an integer of 1 to 3,
R16 and R17 independently of one another represents hydrogen; aryl; lower alkyl which may be optionally substituted by aryl or cyanoaryl; or 
xe2x80x83wherein n4, Q and R10 are defined as previously described,
R18 and R19 independently of one another represents hydrogen; halogen; hydroxy; cyano; lower alkyl; lower alkoxy; alkoxyalkyl; alkylthio; hydroxycarbonyl; aminocarbonyl; aminothiocarbonyl; alkylsulfonyl; alkylthioalkyl; alkylthioalkyloxy; aryl; or oxy, thio, sulfonyl or lower allyl substituted by aryl,
G represents a radical selected by the following group: 
wherein
R11 and R12 are defined as previously described,
I represents lower alkoxy, or represents a radical selected from the following group: 
wherein
R16, R17 and Z are defined as previously described,
L represents a radical selected from the following group: 
wherein Z and Q are defined as previously described,
provided that (1) n2 is other than 0 when R3 is hydrogen, and
(2) Y is other than 
xe2x80x83when A is 
Particularly preferred compounds include those wherein Y represents 
and C represents 
Typical examples of the compound of formula (1) according to the present invention are presented in the following Table 1.
It is another object of the present invention to provide processes for a perparing the imidazole derivative of formula (1) as defined above.
According to the present invention, the imidazole derivative of formula (1) can be prepared by processes characterized in that
(a) a compound represented by the following formula (2) is reacted in a solvent in the presence of a base with a compound represented by the following formula (3), then the trityl group in the product thus obtained is eliminated in the presence of trifluoroacetic acid to produce a compound represented by the following formula (1a); or 
(b) a compound represented by the following formula (4) is reacted in a solvent in the presence of a base with the compound of formula (3) to produce a compound represented by the following formula (1b); or 
(c) a compound represented by the following formula (5) is reacted in a solvent in the presence of a base with the compound of formula (3), the trityl group in the product thus obtained is eliminated in the presence of trifluoroacetic acid to produce a compound represented by the following formula (6), and then hydrogenation reaction is carried out to produce a compound represented by the following formula (1c); or 
(d) a compound represented by the following formula (7) is hydrolyzed to produce a compound represented by the following formula (8) which is then reacted with a compound represented by the following formula (9) in the presence of a coupling agent to produce a compound represented by the following formula (1d); or 
(e) the carbonyl group in a compound represented by the following formula (1e) is converted into the thiocarbonyl group in the presence of a sulfurizig agent to produce a compound represented by the following formula (1f); or 
(f) a compound represented by the following formula (1g) is coupled in a solvent with a compound represented by the following formula (10) to produce a compound represented by the following formula (1h); or 
(g) a compound represented by the following formula (11) is cyclized in an inert solvent to produce a compound represented by the following formula (1i); or 
(h) the amide group in the compound of formula (11) is converted into the thioamide group to produce a compound represented by the following formula (12) which is then cyclized in an inert solvent to produce a compound represented by the following formula (1j); or 
(i) a compound represented by the following formula (13) is reacted in a solvent with a compound represented by the following formula (14a) to produce the compound of formula (1j); or 
(j) the compound of formula (13) is reacted in a solvent with a compound represented by the following formula (14b) to produce a compound represented by the following formula (1k); or 
(k) a compound represented by the following formula (1l) is hydrolyzed in the presence of a base and the product thus obtained is reacted in a solvent in the presence of a coupling agent with a compound represented by the following formula (15) to produce a compound represented by the following formula (1m); or 
(l) a compound represented by the following formula (16) is reacted in a solvent in the presence of a base with a compound represented by the following formula (17) to produce a compound represented by the following formula (1n); or 
(m) a compound represented by the following formula (18) is reacted in a solvent in the presence of a base with the compound of formula (17) and deprotected to produce a compound represented by the following formula (1o) which is then coupled with a compound represented by the following formula (19) to produce a compound represented by the following formula (1p): 
xe2x80x83in the above reaction schemes
A, n1, B, C, X, D, R16, R17, R2, G, I, L, E and F are defined as previously described,
Ixe2x80x2 represents lower alkoxy,
Ixe2x80x3 is identical with I except that lower alkoxy is not included,
T represents hydroxy or reactive leaving group, preferably halogen,
Tr represents trityl,
Cbz represents benzvloxycarbonyl and has the same meaning through the present specification.
However, the compound according to the present invention may be conveniently prepared by any methods designed by combining various synthetic ways known in the prior arts, and such combination can be easily performed by a person having ordinary skill in this art. The processes (a) to (m) will be more specifically explained in below.
In processes (a) to (e) for proparing the compound according to the present invention, any inert solvents which does not adversely affect to the reaction, preferably one or more selected from a group consisting of dimethylformamide, dimethylacetamide, ethanol, water, methylene chloride, chloroform, tetrahydrofuran and N-methylpyrrolidinone can be used. As the base, one or more selected from a group consisting of sodium hydride, potassium hydroxide, potassium carbonate, potassium t-butoxide, sodium amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide, more preferably sodium hydride or potassium hydroxide can be mentioned. As the coupling agent used in the process for reacting the compound of formula (8) with the compound of formula (9), a mixture of 1-hydroxybenzotrizole and one or more substances selected from a group consisting of carbodiimides such as dicyclohexylcarbodiimide(DCC), 1-ethyl-3,3-dimethylaminopropyl)carbodiimide(EDC), 1,1xe2x80x2-dicarbonyldiimidazole(CDI), etc., and inorganic dehydrating agent such as silicone tetrachloride can be mentioned. Among them, a mixture of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC) and 1-hydroxybenzotrizole hydrate is particularly preferred.
The sulfurizing agent used in preparing the compound of formula (1f) from the compound of formula (1e) includes 2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatane-2,4-disulfide, Lawesson""s Reagent and P4S10. 2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatane-2,4-disulfide can be used most preferably.
The compound of formula (1g) which is used as a starting material in process (f) can be prepared by deprotecting the corresponding compound which is protected by benzyloxycarbonyl group at position-1 of piperdine moiety. The deprotection reaction may be carried out by applying the conventional reaction conditions, preferably by using Pd(OH)2/C or Pd/C in an alcohol solvent under hydrogen atmosphere. The compound of formula (1g) thus obtained is coupled with the compound of formula (10) in an inert solvent as mentioned above optionally in the presence of a tertiary amine base to produce the compound of formula (1h). Alternatively, the comound of formula (1g) can be reacted in the presence of a coupling agent as mentioned for process (d) with the carboxylic acid derivative(T=OH) to produce the compound of formula (1h) in the form of amide.
In the cyclization reactions of (g) and (h) for preparing the compounds (1i) and (1j), any inert solvents, preferably one or more selected from tetrahydrofuran and ethanol can be used. As the sulfurizing agent used in the conversion procedure of amide to thioamide group in process (h), 2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphatane-2,4-disulfide, Lawesson""s Reagent or P4S10, preferably Lawesson""s Reagent can be mentioned.
In processes (i) and (j) for preparing the compounds (1j) and (1k) by reacting the compound of formula (13) with the compound of formula (14a) or (14b), one or more solvents selected from ethanol and isopropyl alcohol can be used. Also, ordinary inorganic base, such as for example, one or more selected from a group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably lithium hydroxide can be used in the process (k) wherein the compound of formula (1l) is hydrolyzed and then reacted with the compound of formula (15) to produce the compound of formula (1m). As the coupling agent, those mentioned for process (d) can be used.
In processes (l) and (m), any inert solvents, preferably one or more selected from dimethylformamide and dimethylacetamide are used as the solvent, and one or more selected from a group consisting of sodium hydride, sodium amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide are used as the base. The deprotection reaction in process (m) may be carried out under the conventional reaction conditions for deprotection, preferably in the presence of Pd/C or Pd(OH)2/C under hydrogen atmosphere. Further, the coupling agent used for the coupling of the compound of formula (1o) with the compound of formula (19) may be the same with those mentioned for process (d).
The compound of formula (3) used as the key intermediate in processes (a) to (c) for preparing the compound of formula (1) according to the present invention is itself a novel compound. Therefore, it is another object of the present invention to provide the compound of formula (3). As depicted in the following Reaction Schemes 14 to 16, the compound of formula (3) can be prepared by a process characterized in that a compound represented by the following formula (20) is reacted in a solvent in the presence of a coupling agent with a compound represented by the following formula (21); the compound of formula (20) is reacted in a solvent in the presence of dimethylformamide(DMF) with thionyl chloride to produce a compound represented by the following formula (20a) and then the compound of formula (20a) thus obtained is reacted in a solvent with the compound of formula (21); or a compound represented by the following formula (3a) is oxidized in a solvent to produce a compound represented by the following formula (3b). 
in the above Reaction Shemes 14, 15 and 16
B, C and D are defined as previously described,
Qa represents S or Sxe2x95x90O.
In the above processes according to Reaction Scheme 14 to 16 for preparing the compound (3), any inert solvents, preferably one or more selected from dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran and 1,2-dichloroethane are used as the solvent. As the coupling agent in Reaction Scheme 14, a mixture of 1-hydroxybenzotrizole and one or more substances selected from a group consisting of carbodiimides such as dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(EDC), etc. can be mentioned. Among them, a mixture of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) and 1-hydroxybenzotrizole hydrate is particularly preferred. The dimethylformamide in the process of Reaction Scheme 15 is used in a catalytic amount. Also, excess metachloroperbenzoic acid is preferably used as the oxidant in the process according to the Reaction Scheme 16. However, the coupling agent, oxidant, solvent, catalyst, etc. may be appropriately selected beyond those as mentioned above as far as the purpose of the reaction can be accomplished. And the reaction conditions including the amount of reactants, reaction temperature, reaction time, etc. can easily be determined by a person skilled in this art depending on the specific reactants.
Since the compound of formula (8) which is used as an intermediate for preparing the compound of formula (1d) in process (d) is also a novel compound like the compound of formula (3), it is another object of the present invention to provide the intermediate compound of formula (8). It can be obtained by hydrolyzing the compound of formula (7).
On the other hand, the starting materials used in the above processes can be prepared according to the specific processes described in the following Reaction Schemes 17 to 29.
First, the compound of formula (2) can be obtained through protection and halogenation as depicted in the following Reaction Scheme 17. 
The compound of formula (4) wherein A is 4-cyanobenzyl may be synthesized through protection, acetylation, coupling, deprotection and halogenation as depicted in the following Reaction Scheme 18. More frequently, the compound (4) is prepared by a process wherein an amine compound is reacted with dihydroxyacetone to produce a mercaptoimidazole derivative, which is then desulfurized and halogenated as depicted in the following Reaction Scheme 19. J. Med. Chem., 33, 1312-1329, 1990 in which a similar reaction is explained in detail can be referred to for the specific reaction conditions. 
The amine compound used in the above Reaction Scheme 19 wherein A represents 1-(bemzyloxycarbonyl)piperidine-4-ylmethyl may be synthesized from 4-aminomethylpiperidine through protection, benzyloxycarbonylation and deprotection as depicted in Reaction Scheme 20. 
in the above Reaction Scheme 20
CbzCl represents benzylchloroformate and has the same meaning through the present specification.
The compound of formula (5) may be synthesized through estenfication, protection, reduction and halogenation as depicted in the following Reaction Scheme 21. 
in the above Reaction Scheme 21
DIBAL represents diisobutylaluminumhydride.
Also, in the above Reaction Scheme 21, the alcohol compound obtained before preparing the final chloride compound may be reduced according to the conventional manner and then reacted with thionyl chloride to produce the compound of formula (2) wherein ni is 3.
The compound of formula (20) used as a starting material in preparing the intermediate of formula (3) may be prepared, for example, according to a process described in the following Reaction Scheme 22, a process starting from 1-naphthaldehyde. Particularly, the intermediate of formula (3) wherein D is 1-naphthyl can be conveniently synthesized according to the following reactions of Schemes 23 and 24. 
The compound of formula (11) used as a starting material in process (g) can be prepared by coupling a hydrochloride salt of glycinate derivative with a hydrochloride salt of 4-imidazoleacetic acid, as represented in the following Reaction Scheme 25. As the coupling agent, those mentioned in process (d) can be used. While, the compound of formula (13) used in process (i) may be prepared according to the procedure described in the following Reaction Scheme 26 in which the chloride derivative obtained in the process of Reaction Scheme 19 is used as a starting material. 
The compounds (14a) and (14b) used in processes (i) and (j) can be prepared according to the following Reaction Schemes 27 and 28, respectively. First, the compound of formula 14a can be synthesized by reacting an aldehyde derivative with methyl dichloroacetate in the presence of potassium t-butoxide. The compound of formula (14b) wherein I is Ixe2x80x2 can be synthesized by reacting a ketone derivative with a dialkylcarbonate in the presence of sodium hydride, then by reacting the product thus obtained with sulfuryl chloride. 
Finally, the reactant of formula (17) in process (l) and (m) wherein G represents 1-naphthyl and L represents N-methyl-N-(2-methoxyethyl)amino may be prepared from 1-naphthaldehyde according to the following Reaction Scheme 29. The other compounds (17) having different substituents may also be prepared by referring to Reaction Scheme 29. 
The compound of formula (1) prepared according to the processes above shows an inhibitory activity against farnesyl transferase, and thus can be effectively used as an anti-cancer agent. Therefore, the present invention also provides a pharmaceutical composition comprising the novel compound of formula (1), as defined above, or a pharmaceutically acceptable salt or an isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. Particularly, the compound of formula (1) can be used very effectively for treating cancer, restenosis, atherosclerosis and infections from hepatitis delta and related viruses.
When the active compound according to the present invention is used for clinical purpose, it is preferably administered in an amount ranging from 10 mg to 100 mg per kg of body weight a day. The total daily dosage may be administered in one time or over several times. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight of the subject patient, sex, hygienic condition, diet, time or method of administration, excretion rate, mixing ratio of the agent, severity of the disease to be treated, etc.
The compound of the present invention may be administered in the form of injections or oral preparations. Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing injections include water, Ringer""s fluid and NaCl solution, and also sterilized fixing oil may be conveniently used as the solvent or suspending media. Any non-stimulative fixing oil including mono-, di-glyceride may be used for this purpose. Fatty acid such as oleic acid may also be used for injections.
As the solid preparation for oral administration, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. It is also desirable for tablets and pills to be formulated into enteric-coated preparation. The solid preparations may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent and binding agent.